Neuroprotective Effects of σ2R/TMEM97 Receptor Modulators in Neuronal Model of Huntington's Disease

25 May 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Huntington's disease (HD) is a genetic neurodegenerative disease caused by an expanded CAG repeat in the human Huntingtin gene (HTT) that yields an expanded polyglutamine (polyQ) repeat in exon-1 of the human mutant huntingtin (mHTT) protein. The presence of this polyQ repeat results in neuronal degeneration, and there is no cure nor treatment that modifies disease progression. Small molecules that bind selectively to the recently-cloned sigma 2 receptor (2R), which is identical to TMEM97, have been shown to have neuroprotective effects in Alzheimer's disease, traumatic brain injury and several other neurological disorders. To assess whether modulating pathways involving 2R/TMEM97 can provide protection in HD, we used an HD cell model to evaluate the effects of 2R/TMEM97 ligands on mHTT induced neuronal toxicity. We first synthesized a set of compounds designed to bind to 2R/TMEM97, and binding profiles (Ki) of these ligands were determined. Modulators with high selectivity for 2R/TMEM97 relative to 1Rwere then tested in our HD cell model. Primary cortical neurons were cultured in vitro for seven days and then co-transfected with either normal HTT construct (Htt N-586-22Q/GFP) or mHTT construct (Htt-N586-82Q/GFP). Transfected neurons were treated with 2R/TMEM97 or 1R modulators for 48 h. After treatment, neurons were fixed and stained with Hoechst, and condensed nuclei were quantified to assess cell death in transfected neurons. Significantly, 2R/TMEM97 modulators reduce the neuronal toxicity induced by mHTT, and their neuroprotective effects are not blocked by NE-100, a selective 1R antagonist. These results indicate for the first time that 2R/TMEM97 modulators can protect neurons from mHTT induced neuronal toxicity, suggesting that targeting 2R/TMEM97 may provide a novel therapeutic approach to treat HD patients.


Huntington's disease
neuronal survival
nucleus condensation


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